JP2010514725A - GLYT1 in crystalline form - Google Patents

Abstract

The present invention relates to [4- (3-fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2 -Trifluoro-1-methyl-ethoxy) -phenyl] -methanone relates to four different crystalline and amorphous forms and their use in the manufacture of pharmaceutical compositions. The compounds of the present invention are useful for the treatment of psychosis, pain, neurodegenerative dysfunction in memory and learning, schizophrenia, dementia, and other diseases in which cognitive processes are impaired, such as attention deficit disorder or Alzheimer's disease Suitable for manufacturing.

Description

  The present invention relates to [4- (3-fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2 -Trifluoro-1-methyl-ethoxy) -phenyl] -methanone relates to four different crystalline and amorphous forms and their use in the manufacture of pharmaceutical compositions.

  [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro- 1-methyl-ethoxy) -phenyl] -methanone has already been described in PCT patent application publication number WO 2005/014563.

  [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro- The four different crystalline and amorphous forms of 1-methyl-ethoxy) -phenyl] -methanone are suitable for producing pharmaceutical formulations.

  In a first aspect, the present invention provides the following compound:

3 different crystal forms A, B and C.

  In another aspect, the invention provides [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S)- Relates to the amorphous form of 2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone.

  In another aspect, the invention provides [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S)- Methylparaben co-crystal form of 2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone.

  In a further aspect, the present invention relates to [4- (3-fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S)-). 2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone in a crystalline form A, B, C or an amorphous form or a methylparaben co-crystal form as an active ingredient.

  In a further aspect, the present invention is for the treatment of psychosis, pain, neurodegenerative dysfunction in memory and learning, schizophrenia, dementia, and other diseases in which cognitive processes are impaired, such as attention deficit disorder or Alzheimer's disease. [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S)-) for the manufacture of a useful medicament. 2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone relates to the use of crystalline form A, B, C or amorphous form or methylparaben co-crystal form.

  The aforementioned solid forms can be distinguished by physical and chemical properties, which can be characterized by infrared spectrum, powder X-ray diffraction pattern, melting behavior or glass transition temperature.

[4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro- 1 shows an XRPD (powder X-ray diffraction) pattern of a representative lot of Form A of 1-methyl-ethoxy) -phenyl] -methanone. [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro- 1 shows an IR (infrared spectroscopy) spectrum of a representative lot of Form A of 1-methyl-ethoxy) -phenyl] -methanone. [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro- 1 shows a DSC (Differential Scanning Calorimetry) curve of a representative lot of Form A of 1-methyl-ethoxy) -phenyl] -methanone. [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro- 1 shows a TGA (thermogravimetric analysis) curve of a representative lot of Form A of 1-methyl-ethoxy) -phenyl] -methanone. [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro- 1 shows an XRPD (powder X-ray diffraction) pattern of a representative lot of Form B of 1-methyl-ethoxy) -phenyl] -methanone. [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro- 1 shows an IR (infrared) spectrum of a representative lot of Form B of 1-methyl-ethoxy) -phenyl] -methanone. [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro- 1 shows a DSC (Differential Scanning Calorimetric) curve of a representative lot of Form B of 1-methyl-ethoxy) -phenyl] -methanone. [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro- 1 shows a TGA (thermogravimetric analysis) curve of a representative lot of Form 1 of 1-methyl-ethoxy) -phenyl] -methanone. [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro- 1 shows an XRPD (powder X-ray diffraction) pattern of a representative lot of Form C of 1-methyl-ethoxy) -phenyl] -methanone. [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro- 1 shows an IR (infrared) spectrum of a representative lot of Form C of 1-methyl-ethoxy) -phenyl] -methanone. [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro- 1 shows a DSC (Differential Scanning Calorimetry) curve of a representative lot of Form C of 1-methyl-ethoxy) -phenyl] -methanone. [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro- 1 shows a TGA (thermogravimetric analysis) curve of a representative lot of Form C of 1-methyl-ethoxy) -phenyl] -methanone. [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro- 1 shows an XRPD (powder X-ray diffraction) pattern of a representative lot of amorphous form of 1-methyl-ethoxy) -phenyl] -methanone. [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro- 1 shows the IR (infrared) spectrum of a representative lot of amorphous form of 1-methyl-ethoxy) -phenyl] -methanone. [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro- 2 shows DSC (Differential Scanning Calorimetry) curves of two representative lots of amorphous form of 1-methyl-ethoxy) -phenyl] -methanone. [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro- 1 shows a TGA (thermogravimetric analysis) curve of a representative lot of amorphous form of 1-methyl-ethoxy) -phenyl] -methanone. [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro- 2 shows the DVS (dynamic vapor adsorption) isotherm of a representative lot of amorphous form of 1-methyl-ethoxy) -phenyl] -methanone. [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro- 1 shows an XRPD (powder X-ray diffraction) pattern of a representative lot of methylparaben co-crystal form of 1-methyl-ethoxy) -phenyl] -methanone. [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro- 1 shows the IR (infrared) spectrum of a representative lot of methylparaben co-crystal form of 1-methyl-ethoxy) -phenyl] -methanone. [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro- 1 shows a DSC (Differential Scanning Calorimetry) curve of a representative lot of methylparaben co-crystal form of 1-methyl-ethoxy) -phenyl] -methanone. [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro- 1 shows a TGA (thermogravimetric analysis) curve of a representative lot of methylparaben co-crystal form of 1-methyl-ethoxy) -phenyl] -methanone.

  As used herein, “amorphous form” or “amorphous” refers to a material that lacks long-range order and does not itself exhibit a sharp X-ray peak (ie, Bragg diffraction peak). The XRPD pattern of amorphous material is characterized by one or more amorphous halos.

Bragg's law expresses the diffraction of a crystalline material:
2d sinθ = nλ
(Where d = vertical distance between a pair of adjacent faces in the crystal (d-spacing), θ = Bragg angle, λ = wavelength, and n = integer)
I will explain it.

  If Bragg's law is satisfied, the reflected beam is in phase and structurally interferes, so a Bragg diffraction peak is observed in the X-ray diffraction pattern. At incident angles other than the Bragg angle, the reflected beam is in antiphase and destructive interference or cancellation occurs. The amorphous material does not satisfy Bragg's law, and no Bragg diffraction peak is observed in the X-ray diffraction pattern.

  An “amorphous halo” is a generally diffraction peak maximum diffraction within the powder X-ray diffraction pattern of an amorphous material. The FWHM of the amorphous halo has 2θ greater than 2 °.

  “FWHM” means the full width at half maximum, that is, the width at half the height of the peak seen in the XRPD pattern.

  “API” is used herein as an acronym for active pharmaceutical ingredient.

  “DSC” is used herein as an acronym for differential scanning calorimetry. Mettler-Toledo ™ differential scanning calorimeter: DSC curve was recorded using DSC820 or DSC821 equipped with FRS05 sensor. Instrument suitability testing and calibration were performed according to internal standard operating procedures.

  For measurement of crystal form, about 2-6 mg of sample was placed in an aluminum container, accurately weighed and sealed with perforation lids. Before the measurement, a pinhole of about 1.5 mm was opened through the lid automatically. The sample was then heated using a heating rate of 10 K / min under a nitrogen flow of about 100 mL / min.

  For measurement of the amorphous form, approximately 2-6 mg of sample was placed in an aluminum container and accurately weighed and sealed. The sample was then heated using a heating rate of 10 K / min under a nitrogen flow of about 100 mL / min.

  “DVS” is used herein as an acronym for dynamic vapor adsorption. The DVS isotherm was collected with a DVS-1 (SMS: surface measuring device) moisture balance device. The adsorption / desorption isotherm was measured stepwise within the range of 0% RH to 90% RH at 25 ° C. A weight change of <0.002 mg / min was selected as a criterion to switch to the next level of relative humidity (if the weight criterion was not met, a maximum equilibration time of 6 hours was used). The data was corrected for the initial moisture content of the sample, ie, the weight after drying the sample at 0% relative humidity was 0 points.

  “Form A” refers herein to [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S ) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone is used as an abbreviation for crystal form A.

  “Form B” refers herein to [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S ) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone is used as an abbreviation for crystalline form B.

  “Form C” refers herein to [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S ) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone is used as an abbreviation for crystalline form C.

  “Methylparaben co-crystal form” is referred to herein as [4- (3-fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2- ( (S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone is used as an abbreviation for the methylparaben co-crystal form.

“IR” is used herein as an acronym for infrared, and therefore “IR spectrum” means infrared spectrum. The IR spectrum of the sample was recorded in transmission using a FT-IR spectrometer as a film of Nujol suspension consisting of about 5 mg of sample and a little Nujol between two sodium chloride plates. The spectrometer was Nicolet ™ 20SXB or equivalent (resolution 2 cm ⁻¹ , 32 or more coded scans, MCT detector).

  “XRPD” is used herein as an acronym for powder X-ray diffraction. X-ray diffraction patterns are recorded by STOE STADI P diffractometer at ambient conditions of transmission arrangement (CuKα irradiation, primary monochromator, position sensitive detector, angle range 3 to 42 2θ (°), total measurement time about 60 minutes) It was done. Samples were prepared and analyzed without further processing (eg, grinding or sieving) of the material.

  Alternatively, X-ray diffraction patterns were recorded in transmission configuration with a STOE STADI P diffractometer equipped with CuKα irradiation (1.54 mm) and a position sensitive detector. Samples (about 50 mg) were prepared between thin polymer (or aluminum) films and analyzed without further processing (eg, grinding or sieving) of the material.

  X-ray diffraction patterns were also measured with a Scintag X1 powder X-ray diffractometer equipped with a sealed copper-Kα1 irradiation source. Samples were scanned from 2 to 36 2θ (°) at a rate of 1 ° 2θ per minute with incident beam slit widths of 2 and 4 mm and diffracted beam slit widths of 0.3 and 0.2 mm.

  In the single crystal structure analysis, the single crystal was placed in a goniometer loop and measured at ambient conditions. Alternatively, the crystals were cooled in a stream of nitrogen between measurements. Data were collected on a STOE imaging plate diffractometer (IPDS) from STOE (Darmstadt). In this case, 0.71 mm wavelength Mo irradiation was used for data recovery. Data were processed with STOE IPDS software. The crystal structure was elucidated and refined with standard crystallography software. In this case, Bruker AXS (Karlsruhe) program: ShelXTL was used.

  Alternatively, synchrotron radiation was used for data collection. The single crystal was placed in a loop and cooled to about 100K in a nitrogen stream. Data was collected using a MAR CCD225 detector with synchrotron radiation at the Swiss Light Source beamline X10SA and processed with the program: XDS. The crystal structure was elucidated and refined with standard crystallography software. In this case, Bruker AXS (Karlsruhe) program: ShelXTL was used. The crystal structure was elucidated and refined with ShelXTL (Bruker AXS, Karlsruhe).

  “TGA” is used herein as an acronym for thermogravimetric analysis. TGA curves were measured with a Mettler-Toledo ™ thermogravimetric analyzer (TGA850 or TGA851). Instrument suitability testing and calibration were performed according to internal standard operating procedures.

  For thermogravimetric analysis, approximately 5-10 mg of sample was placed in an aluminum container, accurately weighed and sealed with a perforated lid. Before the measurement, a pinhole of about 1.5 mm was opened through the lid automatically. The sample was then heated using a heating rate of 5 K / min under a nitrogen flow of about 50 mL / min.

  Pharmaceutically acceptable carriers, excipients, adjuvants, preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavors, salts that vary osmotic pressure, buffers, masking “Pharmaceutically acceptable” such as an agent or antioxidant means pharmaceutically acceptable and substantially non-toxic to the subject to which the particular compound is administered.

  Thus, “pharmaceutically acceptable” means substantially non-toxic to the subject to which the pharmaceutically acceptable material is administered.

  A “co-crystal” is formed between a molecular or ionic API and a co-crystal former that is solid at ambient temperature, ie, the co-crystal is a multi-component crystalline material comprising two or more solids (at ambient temperature). It is.

  “Therapeutically effective amount” means an amount effective to prevent, reduce or ameliorate symptoms of disease or prolong the survival of the subject being treated.

  As already described above, the present invention provides the following compounds:

[4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro- It relates to four novel crystalline and amorphous forms of 1-methyl-ethoxy) -phenyl] -methanone.

  [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro- It has been found that 1-methyl-ethoxy) -phenyl] -methanone can be isolated as Form A, B, C or methylparaben co-crystalline and amorphous forms, depending on the method of manufacture.

  Forms A, B and C are as described below: [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2 -((S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone can be isolated from several different crystallization methods.

  The amorphous form is described in [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2- ( (S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone solution can be obtained by lyophilization or rapid concentration.

  The methyl paraben co-crystal form can be obtained by digestion or recrystallization of Form A, B, C or amorphous form and methyl paraben as described below.

In certain embodiments of the invention, Form A is
-After seeding, [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2 , 2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone,
-Or [4- (3-fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S)- Recrystallizing 2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone and spontaneously crystallizing below about 40 ° C .;
It can manufacture by the method containing any of these.

  In certain embodiments, after seeding, [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5 in ethanol at a specific temperature. -Methanesulfonyl-2-((S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone is recrystallized, concentrated and then crystallized on cooling to form A can be obtained. Usually, [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2- () is added in ethanol without seed crystals. (S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone is recrystallized and spontaneously crystallized below 40 ° C., followed by precipitation on cooling, Form A can be obtained. However, the formation of Form A is not limited to ethanol, ethanol / water, methanol, methanol / water, toluene, 2-propanol, dioxane / water and dioxane.

  These production methods, in particular seed crystal production methods, are further described in the following examples.

  Form A is a solvent-free form because no significant weight loss is observed in the TGA curve prior to degradation.

  Form A has 2θ (°) = approximately: 13.1, 14.3, 15.4, 16.2, 17.1, 17.2, 17.6, 18.0, 19.8, 20.1 20.4, 21.0, 22.6, 24.3 and can be characterized by at least three peaks selected from X-ray diffraction peaks obtained by CuKα irradiation.

  Form A has 2θ (°) = approximately: 13.1, 14.3, 15.4, 16.2, 17.1, 17.2, 17.6, 18.0, 19.8, 20.1 20.4, 21.0, 22.6, 24.3 and can be characterized by at least 5 peaks selected from X-ray diffraction peaks obtained by CuKα irradiation.

  Form A has 2θ (°) = approximately: 13.1, 14.3, 15.4, 16.2, 17.1, 17.2, 17.6, 18.0, 19.8, 20.1 20.4, 21.0, 22.6, 24.3 and can be characterized by at least 7 peaks selected from X-ray diffraction peaks obtained by CuKα irradiation.

  Form A has 2θ (°) = approximately: 13.1, 14.3, 15.4, 16.2, 17.1, 17.2, 17.6, 18.0, 19.8, 20.1 It can also be characterized by the X-ray diffraction peaks obtained with CuKα irradiation, expressed at 20.4, 21.0, 22.6 and 24.3.

  The term “approximately” means herein that there is an uncertainty of ± 0.2 (expressed in 2θ (°)) in the measured value of 2θ (°).

  Form A can also be characterized by the X-ray diffraction pattern substantially shown in FIG.

Form A is 3032, 1645, 1623, 1600, 1581, 1501, 1342, 1331, 1314, 1291, 1266, 1245, 1154, 1130, 1088, 1054, 1012, 976, 951, 922, 889, 824, 787, It can also be characterized by an infrared spectrum with sharp bands at 758, 739, 714 and 636 cm ⁻¹ (± 3 cm ⁻¹ ).

  Form A can also be characterized by an infrared spectrum substantially as shown in FIG.

  Form A can also be characterized by a melting point having an onset temperature (DSC) in the range of about 138 ° C to 144 ° C.

  These features and others are shown in FIGS.

  A single crystal structure analysis of Form A was performed. Table 1 lists some crystal structure data. The experimental XRPD pattern recovered by Form A corresponds to the theoretical pattern calculated from the crystal structure data. In the single crystal structure of Form A, the piperazine ring exhibits a chair-type conformation in which the pyridine substituent is in the equatorial position.

  In one embodiment of the invention, the compound: [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone comprises at least 70% of the crystalline polymorph of Form A described above; in certain embodiments, it comprises Including at least 90% of the described Form A crystalline polymorph; in certain embodiments, it includes at least 96% of the previously described Form A crystalline polymorph; in certain embodiments, It contains at least 99% of the described Form A crystalline polymorph.

In a particular embodiment of the invention, Form B is
-[4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro Putting seed crystals into a solution of -1-methyl-ethoxy) -phenyl] -methanone;
-Or [4- (3-fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S)- Crystallizing a solution of 2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone,
-Or [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S)-) in one or more solvents Recrystallizing 2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone and adding seeds of form B;
It can manufacture by the method containing any of these.

  Form B can be obtained by placing seed crystals in an ethanol solution followed by cooling. Form B can optionally be obtained without seeding the ethanol solution and without subsequent cooling. Form B is also [4- (3-fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S)] in a plurality of solvents. -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone can be prepared by recrystallizing and adding seeds of Form B.

  Form B is a solvent-free form because no significant weight loss is observed on the TGA curve before degradation.

  These production methods, in particular seed crystal production methods, are further described in the following examples.

  Form B has 2θ (°) = approximately: 11.4, 15.4, 16.2, 16.2, 16.4, 17.8, 18.3, 19.2, 20.1, 21.0 22.0, 22.5, 26.4 and can be characterized by at least three peaks selected from the X-ray diffraction peaks obtained by CuKα irradiation.

  Form B has 2θ (°) = approximately: 11.4, 15.4, 16.2, 16.2, 16.4, 17.8, 18.3, 19.2, 20.1, 21.0 22.0, 22.5, 26.4 and can be characterized by at least 5 peaks selected from the X-ray diffraction peaks obtained by CuKα irradiation.

  Form B has 2θ (°) = approximately: 11.4, 15.4, 16.2, 16.2, 16.4, 17.8, 18.3, 19.2, 20.1, 21.0 22.0, 22.5, 26.4 and can be characterized by at least 7 peaks selected from the X-ray diffraction peaks obtained by CuKα irradiation.

  Form B has 2θ (°) = approximately: 11.4, 15.4, 16.2, 16.2, 16.4, 17.8, 18.3, 19.2, 20.1, 21.0 It can also be characterized by the X-ray diffraction peaks obtained by CuKα irradiation, expressed at 22.0, 22.5 and 26.4.

  The term “approximately” means herein that there is an uncertainty of ± 0.2 (expressed in 2θ (°)) in the measured value of 2θ (°).

  Form B can also be characterized by the X-ray diffraction pattern substantially shown in FIG.

Form B includes 1644, 1635, 1621, 1599, 1567, 1514, 1488, 1398, 1343, 1328, 1291, 1266, 1183, 1155, 1090, 1022, 1003, 973, 958, 938, 920, 897, 822, It can also be characterized by an infrared spectrum with sharp bands at 783, 753, 740, 683 and 638 cm ⁻¹ (± 3 cm ⁻¹ ).

  Form B can also be characterized by an infrared spectrum substantially as shown in FIG.

  Form B can also be characterized by a melting point having an onset temperature (DSC) in the range of about 151 ° C. to 154 ° C.

  These features and others are shown in FIGS.

  A single crystal structure analysis of Form B was performed. Table 2 lists some crystal structure data. The experimental XRPD pattern recovered by Form B corresponds to the theoretical pattern calculated from the crystal structure data. In the single crystal structure of Form B, the piperazine ring exhibits a chair-type conformation in which the pyridine substituent is in the axial position.

  In one embodiment of the invention, the compound: [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone comprises at least 70% of the crystalline polymorph of form B described above; in certain embodiments, it comprises Including at least 90% of the described Form B crystalline polymorph; in certain embodiments, it includes at least 96% of the previously described Form B crystalline polymorph; in certain embodiments, Contains at least 99% of the described Form B crystalline polymorph.

In a particular embodiment of the invention, Form C is
-[4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro Crystallizing -1-methyl-ethoxy) -phenyl] -methanone;
-Or by adding a seed crystal of Form C, [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-(( S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone,
-Or [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2) at about 150 <0> C. , 2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone followed by cooling.
It can manufacture by the method containing any of these.

  Form C can be obtained by crystallization at 100 ° C. from toluene or toluene / n-heptane solution. Form C is also [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S)] in a plurality of solvents. -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone and can be prepared by adding a seed of Form C. Further, Form C is [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone can be obtained by tempering at 150 ° C. for 2 hours followed by rapid cooling.

  These production methods, in particular seed crystal production methods, are further described in the following examples.

  Form C is a solvent-free form because no significant weight loss is observed in the TGA curve before degradation.

  Form C has 2θ (°) = approximately: 14.9, 15.7, 16.7, 17.7, 17.8, 18.7, 19.7, 21.8, 22.0, 25.2 Can be characterized by at least three peaks selected from X-ray diffraction peaks obtained by CuKα irradiation.

  Form C has 2θ (°) = approximately: 14.9, 15.7, 16.7, 17.7, 17.8, 18.7, 19.7, 21.8, 22.0, 25.2 Can be characterized by at least 5 peaks selected from X-ray diffraction peaks obtained by CuKα irradiation.

  Form C has 2θ (°) = approximately: 14.9, 15.7, 16.7, 17.7, 17.8, 18.7, 19.7, 21.8, 22.0, 25.2 Can be characterized by at least 7 peaks selected from X-ray diffraction peaks obtained by CuKα irradiation.

  Form C has 2θ (°) = approximately: 14.9, 15.7, 16.7, 17.7, 17.8, 18.7, 19.7, 21.8, 22.0, 25.2 Can be characterized by the X-ray diffraction peaks obtained by CuKα irradiation.

  The term “approximately” means herein that there is an uncertainty of ± 0.2 (expressed in 2θ (°)) in the measured value of 2θ (°).

  Form C can also be characterized by the X-ray diffraction pattern substantially shown in FIG.

Form C includes 1641, 1622, 1601, 1581, 1566, 1514, 1398, 1378, 1341, 1322, 1309, 1294, 1281, 1159, 1087, 1023, 1009, 966, 934, 917, 901, 822, 784, It can also be characterized by an infrared spectrum with sharp bands at 757, 681 and 640 cm ⁻¹ (± 3 cm ⁻¹ ).

  Form C can also be characterized by an infrared spectrum substantially as shown in FIG.

  Form C can also be characterized by a melting point having an onset temperature (DSC) in the range of about 152 ° C to 156 ° C.

  These features and others are shown in FIGS.

  In one embodiment of the invention, the compound: [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone comprises at least 70% of the crystalline polymorph of form C described above; in certain embodiments, it comprises Including at least 90% of the described Form C crystalline polymorph; in certain embodiments, it includes at least 96% of the previously described Form C crystalline polymorph; in certain embodiments, Contains at least 99% of the described Form C crystalline polymorph.

In certain embodiments of the invention, the amorphous form is
-[4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro Rapid evaporation from a solution of -1-methyl-ethoxy) -phenyl] -methanone under reduced pressure at about 40 ° C .;
-Or [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-tri Lyophilizing a solution of fluoro-1-methyl-ethoxy) -phenyl] -methanone;
It can manufacture by the method containing any of these.

  The amorphous form can be obtained from an ethanol solution by rapid evaporation at about 40 ° C. under reduced pressure. The amorphous form is also [4- (3-fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S ) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone can be obtained by lyophilization of a solution of 1.0 g (-46 ° C. and 0-1 mbar vacuum cooler). .

  These preparation methods in amorphous form are further described in the following examples.

  The amorphous form can be characterized by the lack of sharp X-ray diffraction peaks in its XRPD pattern.

  The amorphous form can also be characterized by the X-ray diffraction pattern substantially shown in FIG.

Amorphous forms are 1642, 1622, 1599, 1579, 1509, 1487, 1399, 1329, 1293, 1253, 1159, 1124, 1090, 1016, 960, 920, 903, 889, 827, 782, 763, 739 and It can also be characterized by an infrared spectrum having a sharp band at 636 cm ⁻¹ (± 3 cm ⁻¹ ).

  The amorphous form can also be characterized by an infrared spectrum substantially as shown in FIG.

  The amorphous form can also be characterized by a glass transition temperature (DSC, heating rate 10 K / min, closed pan) of about 48 ° C. to about 65 ° C. (glass transition temperature depends on the solvent / water content. Depends heavily).

  These features and others are shown in FIGS.

  In one embodiment of the invention, the compound: [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone comprises at least 70% of the previously described amorphous form; in certain embodiments, it is In certain embodiments, it includes at least 96% of the previously described amorphous form; in certain embodiments, it includes the amorphous form described above. Contains at least 99% of the form.

  In particular embodiments of the present invention, the methylparaben co-crystal form recrystallizes Form A, B, C or the amorphous form and methylparaben with or without seed crystals in the solvent system. It can manufacture by the method including the process to convert.

  The methylparaben co-crystal form can be produced by digestion in a solvent (eg, ethanol and water). It is produced by recrystallizing Form A, B, C or amorphous form and methylparaben with or without seed crystals in a solvent system containing, but not limited to, ethanol You can also. [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro- The ratio of 1-methyl-ethoxy) -phenyl] -methanone to methylparaben can be in the range of 1: 1 to 1:10.

  These production methods, in particular seed crystal production methods, are further illustrated in the following examples.

  The methyl paraben co-crystal form is 2θ (°) = approximately: 8.0, 8.9, 10.5, 12.6, 15.2, 16.1, 17.7, 18.5, 19.8, 20 2, 21.7, 22.9, 24.2, 25.9 and can be characterized by at least three peaks selected from X-ray diffraction peaks obtained by CuKα irradiation.

  The methyl paraben co-crystal form is 2θ (°) = approximately: 8.0, 8.9, 10.5, 12.6, 15.2, 16.1, 17.7, 18.5, 19.8, 20 2, 21.7, 22.9, 24.2, 25.9 and can be characterized by at least 5 peaks selected from the X-ray diffraction peaks obtained by CuKα irradiation.

  The methyl paraben co-crystal form is 2θ (°) = approximately: 8.0, 8.9, 10.5, 12.6, 15.2, 16.1, 17.7, 18.5, 19.8, 20 .2, 21.7, 22.9, 24.2 and 25.9 can be characterized by at least 7 peaks selected from the X-ray diffraction peaks obtained by CuKα irradiation.

  The methyl paraben co-crystal form is 2θ (°) = approximately: 8.0, 8.9, 10.5, 12.6, 15.2, 16.1, 17.7, 18.5, 19.8, 20 .2, 21.7, 22.9, 24.2 and 25.9 can also be characterized by the X-ray diffraction pattern obtained by CuKα irradiation.

  The term “approximately” means herein that there is an uncertainty of ± 0.2 (expressed in 2θ (°)) in the measured value of 2θ (°).

  The methylparaben co-crystal form can also be characterized by the X-ray diffraction pattern substantially shown in FIG.

The methylparaben co-crystal forms are 3154, 3081, 1709, 1614, 1586, 1378, 1337, 1313, 1247, 1189, 1172, 1124, 1085, 1019, 959, 928, 916, 908, 894, 857, 783, 772, It can also be characterized by an infrared spectrum with sharp bands at 729 and 702 cm ⁻¹ (± 3 cm ⁻¹ ).

  The methylparaben co-crystal form can also be characterized by the infrared spectrum substantially shown in FIG.

  These features and others are shown in FIGS.

  Single crystal structure analysis of methylparaben co-crystal was performed. Table 3 lists some crystal structure data. The experimental XRPD pattern recovered with the methylparaben co-crystal form corresponds to the theoretical pattern calculated from the crystal structure data.

  In one embodiment of the invention, the compound comprises the previously described [4- (3-fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl -2-((S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone comprising at least 70% methylparaben co-crystal form; in certain embodiments, it is as previously described In certain embodiments, it comprises at least 96% of the methylparaben cocrystal described above; in certain embodiments, it comprises the methylparaben cocrystal described above. Contains at least 99%.

  As described above, in one aspect the present invention relates to a pharmaceutical composition comprising as active ingredient one or more of crystalline form A, B, C or methylparaben co-crystal form or amorphous form.

  In addition to one of the crystalline or amorphous forms of the present invention described above, the pharmaceutical composition of the present invention can include a pharmaceutically acceptable carrier. Suitable pharmaceutically acceptable carriers include pharmaceutically inert inorganic and organic carriers. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used as carriers for eg tablets, coated tablets, dragees and hard shell capsules. Suitable carriers for soft shell capsules are, for example, vegetable oils, waxes, fats, semisolid and liquid polyols and the like. However, depending on the nature of the active substance, carriers are usually not required in the case of soft gelatin capsules. Suitable carriers for solutions include, for example, water, polyols, sucrose, invert sugar, glucose and the like.

  The active ingredient can be incorporated at a low or high concentration in a composition further comprising conventional pharmaceutically acceptable adjuvants known in the art.

  These pharmaceutical compositions can be in the form of tablets, coated tablets, dragees, hard and soft shell capsules, solutions, emulsions or suspensions. The present invention also provides a process for the preparation of such a composition comprising the aforementioned improvements and forms in the dosage form of a galenical formulation together with one or more therapeutically inert carriers.

  In addition, the pharmaceutical composition comprises pharmaceutically acceptable preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavors, salts that vary osmotic pressure, buffers, masking agents. Or an antioxidant can be included. They can also contain other therapeutically valuable substances.

  The dosage to administer the active ingredient, i.e. the crystalline or amorphous form of the invention, can vary within wide limits and must of course be adapted to the individual requirements of the individual case. For oral administration, the dosage for adults can vary from about 0.01 mg to about 1000 mg, preferably from about 1 mg to about 240 mg, more preferably from about 3 mg to about 120 mg per day. The daily dose may be administered as a single dose or in divided doses, and in addition, the upper limit may be exceeded if the need is indicated.

  The following table of this specification shows examples of typical capsule formulations that can be produced according to the present invention.

Prescription
Capsule formulation (wet granulation)

Manufacturing procedure Mix items 1, 2, 3, 4 and 5 with a suitable mixer.
2. Granulate the mixed powder from step 1 with the granulating liquid.
3. The mixture obtained from step 2 is screened, dried and the granules are sieved.
4). Items 6 and 7 are added to the dried and sieved granules from step 3 and mixed.
5). Fill the mixture from step 4 into suitable capsules.

Examples Preparation of compounds according to the invention Example 1
Preparation of Form A
Overview Form A can be prepared in a solvent such as methanol, ethanol, 2-propanol, isopropyl acetate, t-butyl methyl ether, toluene, or acetone / water (eg, 1: 1, w / w), water / methanol. (Eg 1: 1, w / w), by digestion in a solvent mixture such as water / ethanol (eg 0.4: 0.6, w / w). [4- (3-Fluoro-, with or without seed crystals in a solvent system including but not limited to ethanol, water / ethanol (eg, 0.6: 0.4, w / w) 5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl It can also be prepared by recrystallizing the methanone.

Crystallization Procedure [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2- 30.0 g of trifluoro-1-methyl-ethoxy) -phenyl] -methanone was dissolved in 150 g of ethanol and heated to 70 ° C. The solution was filtered hot. The temperature was lowered to 40-42 ° C. At 40-42 ° C., [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2 , 2-Trifluoro-1-methyl-ethoxy) -phenyl] -methanone 300 mg of Form A seed crystals was added. The temperature was held at 40-42 ° C. for 1 hour. Subsequently, the suspension was cooled to 0-5 ° C. at 0.3 K / min. After stirring at 0-5 ° C for 1 hour, the crystals were filtered, washed with about 20 mL of ethanol (0-5 ° C) and dried at 50 ° C / 0-20 mbar for 14 hours. Yield: 26.31 g (87.7%).

Preparation of Form A Seed Crystals Form A seed crystals were prepared in a solvent system comprising, but not limited to, ethanol, methanol and an ethanol / water water mixture (eg, 0.4: 0.6 w / w) [4 -(3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro-1- It can be prepared by digesting a slurry of methyl-ethoxy) -phenyl] -methanone. After stirring the slurry for several days at room temperature, the Form A crystals could be filtered and dried at 50 ° C./0-20 mbar for 14 hours. It may be necessary to repeat this procedure several times.

Form A solid state characteristics Form A XRPD pattern, IR spectrum, DSC curve, and TG curve are shown in FIGS.

Example 2
Preparation of Form B
Summary [4- (3-Fluoro-5-trifluoromethyl-pyridine] with or without seed crystals in different solvent systems including methanol, ethanol, 1,4-dioxane and mixtures of these waters -2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone By doing so, Form B can be prepared.

Crystallization Procedure [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2- 30.0 g of trifluoro-1-methyl-ethoxy) -phenyl] -methanone was dissolved in 150 g of ethanol and heated to 60 ° C. [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro- Dissolution of 1-methyl-ethoxy) -phenyl] -methanone occurred at 55-57 ° C. The solution was filtered hot. The temperature was lowered to 40-42 ° C. At 40-42 ° C., [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2 , 2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone, Form B seed crystals, 3.0 g (10% -w) were added to the clear solution. The suspension was subsequently cooled to 5 ° C. within 5 hours. The crystals were filtered, washed with about 10 mL of ethanol (0 ° C.) and dried at 50 ° C./0-20 mbar for 14 hours. Yield (yield): 29.17 g (88.4%).

Preparation of Form B Seed Crystals [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-in a solvent system including but not limited to ethanol, tetrahydrofuran, toluene or 1,4-dioxane By rapidly cooling a highly saturated solution of piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone Form B seed crystals can be prepared.

  [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro- 3.0 g of 1-methyl-ethoxy) -phenyl] -methanone was dissolved in 9 g of ethanol and heated to 70 ° C. The solution was filtered hot. The temperature of the clear solution was rapidly reduced to 0-5 ° C. The crystals were filtered, washed with about 20 mL of ethanol (0-5 ° C.) and dried at 50 ° C./0-20 mbar for 14 hours. It may be necessary to repeat this procedure several times.

Solid State Characteristics of Form B The XRPD pattern, IR spectrum, DSC curve and TG curve of Form B are shown in FIGS.

Example 3
Preparation of Form C
Summary Form C is digested in a solvent such as n-heptane, toluene, o-xylene, or in a solvent mixture such as n-heptane / toluene (eg 1: 0.8, w / w). Can be manufactured. In a different solvent system, seed crystals were placed in [4- (3-fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-(( It can also be prepared by recrystallizing S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone.

Crystallization Procedure [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2- 45.0 g of trifluoro-1-methyl-ethoxy) -phenyl] -methanone was digested in 43.4 g of toluene and 54.7 g of n-heptane and heated to 98-100 ° C. The suspension was stirred at 98-100 ° C. for 48 hours. The suspension was filtered hot. The resulting solid residue was dried at 70 ° C./0-20 mbar for 24 hours. Yield (yield): 23.0 g (51.5%).

Solid state characteristics of Form C The XRPD pattern, IR spectrum, DSC curve and TG curve of Form C are shown in FIGS.

Example 4
Preparation of amorphous form
A general amorphous form could be obtained from an ethanol solution by rapid evaporation at about 40 ° C. under reduced pressure. [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro- A further amorphous form of 1-methyl-ethoxy) -phenyl] -methanone could be obtained by lyophilization.

Preparation Procedure [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-tri 0.50 g of fluoro-1-methyl-ethoxy) -phenyl] -methanone was dissolved in 50 g of ethanol at 65 ° C. Maximum vacuum was applied while rotating at 40 ° C. (rotary evaporator). After complete evaporation of the solvent, the solid was further dried at about 25 ° C / 5-20mbar for 18 hours. Analysis was performed on amorphous [4- (3-fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2, 2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone.

Solid State Characteristics of Amorphous Form Amorphous XRPD pattern, IR spectrum, DSC curve, TG curve and moisture adsorption / desorption isotherm are shown in FIGS.

Example 5
Preparation of methylparaben co-crystal form
Summary [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro A co-crystal of -1-methyl-ethoxy) -phenyl] -methanone and methylparaben can be prepared by digestion in a solvent such as ethanol and water. [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl with or without seed crystals in a solvent system including but not limited to ethanol ]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone in the form A, B, C or amorphous form and methylparaben It can also be prepared by recrystallization. [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro- The range of the 1-methyl-ethoxy) -phenyl] -methanone: methylparaben ratio can be 1: 1 to 1:10.

Preparation Procedure [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-tri 100 mg of fluoro-1-methyl-ethoxy) -phenyl] -methanone and 28 mg of methylparaben ([4- (3-fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methane Sulfonyl-2-((S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone 1 part + methyl paraben 1 part) is dissolved in 0.3 mL of ethanol and both substances are dissolved. Until heated. The clear solution was cooled to room temperature without stirring. After 7 weeks, the crystals were filtered, washed with ethanol / water (60/40 w / w) and dried at room temperature / 0-20 mbar for 14 hours.

Solid state characteristics of methyl paraben co-crystal form XRPD pattern, IR spectrum, DSC curve and METG curve of methyl paraben co-crystal are shown in FIGS.

Claims (33)

  2θ (°) = 13.1, 14.3, 15.4, 16.2, 17.1, 17.2, 17.6, 18.0, 19.8, 20.1, 20.4, 21 0.0, 22.6 and 24.3 (± 0.2), characterized by at least three peaks selected from X-ray diffraction peaks obtained by CuKα irradiation [4- (3- Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro-1-methyl-ethoxy) Crystal form A of -phenyl] -methanone.   2θ (°) = 13.1, 14.3, 15.4, 16.2, 17.1, 17.2, 17.6, 18.0, 19.8, 20.1, 20.4, 21 [4- (3-Fluoro-5-trifluoromethyl-pyridine, characterized by X-ray diffraction peaks obtained with CuKα irradiation, expressed in 0.0, 22.6 and 24.3 (± 0.2)] 2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone crystal form A .   [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl, characterized by the X-ray diffraction pattern substantially shown in FIG. Crystal form A of -2-((S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone. 3032, 1645, 1623, 1600, 1581, 1501, 1342, 1331, 1314, 1291, 1266, 1245, 1154, 1130, 1088, 1054, 1012, 976, 951, 922, 889, 824, 787, 758, 739, [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl] characterized by an infrared spectrum with sharp bands at 714 and 636 cm ⁻¹ (± 3 cm ⁻¹ ) Crystal form A of [5-methanesulfonyl-2-((S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone.   [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl--characterized by the infrared spectrum substantially shown in FIG. Crystal form A of 2-((S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone.   2θ (°) = 11.4, 15.4, 16.2, 16.4, 17.8, 18.3, 19.2, 20.1, 21.0, 22.0, 22.5 and 26 .4 (± 0.2), characterized by at least three peaks selected from the X-ray diffraction peaks obtained with CuKα irradiation [4- (3-Fluoro-5-trifluoromethyl- Crystal form of pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone B.   2θ (°) = 11.4, 15.4, 16.2, 16.4, 17.8, 18.3, 19.2, 20.1, 21.0, 22.0, 22.5 and 26 [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazine-, characterized by an X-ray diffraction peak obtained by CuKα irradiation, expressed in .4 (± 0.2) Crystal form B of 1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone.   [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl, characterized by the X-ray diffraction pattern substantially shown in FIG. Crystal form B of -2-((S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone. 1644, 1635, 1621, 1599, 1567, 1514, 1488, 1398, 1343, 1328, 1291, 1266, 1183, 1155, 1090, 1022, 1003, 973, 958, 938, 920, 897, 822, 783, 753, [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazine-1-, characterized by an infrared spectrum with sharp bands at 740, 683 and 638 cm ⁻¹ (± 3 cm ⁻¹ ) Yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone.   [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl--characterized by the infrared spectrum substantially shown in FIG. Crystal form B of 2-((S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone.   2θ (°) = 14.9, 15.7, 16.7, 17.7, 17.8, 18.7, 19.7, 21.8, 22.0 and 25.2 (± 0.2) [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazine, characterized by at least three peaks selected from X-ray diffraction peaks obtained by CuKα irradiation expressed in Crystal form C of -1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone.   2θ (°) = 14.9, 15.7, 16.7, 17.7, 17.8, 18.7, 19.7, 21.8, 22.0 and 25.2 (± 0.2) [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-characterized by the X-ray diffraction peak obtained by CuKα irradiation expressed in Crystal form C of methanesulfonyl-2-((S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone.   [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl, characterized by the X-ray diffraction pattern substantially shown in FIG. Crystal form C of -2-((S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone. 1641, 1622, 1601, 1581, 1566, 1514, 1398, 1378, 1341, 1322, 1309, 1294, 1281, 1159, 1087, 1023, 1009, 966, 934, 917, 901, 822, 784, 757, 681 and [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[, characterized by an infrared spectrum with a sharp band at 640 cm ⁻¹ (± 3 cm ⁻¹ ) Crystal form C of 5-methanesulfonyl-2-((S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone.   [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-, characterized by the infrared spectrum substantially shown in FIG. Crystal form C of 2-((S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone. Lack of sharp X-ray peaks in the XRPD pattern and / or 1642, 1622, 1599, 1579, 1509, 1487, 1399, 1329, 1293, 1253, 1159, 1124, 1090, 1016, 960, 920, 903, 889, 827, [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazine-, characterized by an infrared spectrum with sharp bands at 782, 763, 739 and 636 cm ⁻¹ (± 3 cm ⁻¹ ) Amorphous form of 1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone.   [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazine, characterized by a glass transition temperature (DSC, heating rate 10 K / min, sealed vessel) of about 48 ° C. to about 65 ° C. Amorphous form of -1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone.   2θ (°) = 8.0, 8.9, 10.5, 12.6, 15.2, 16.1, 17.7, 18.5, 19.8, 20.2, 21.7, 22 Characterized by at least three peaks selected from X-ray diffraction peaks obtained by CuKα irradiation, expressed in .9, 24.2 and 25.9 (± 0.2) [4- (3- Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro-1-methyl-ethoxy) -Methylparaben co-crystal form of -phenyl] -methanone.   2θ (°) = 8.0, 8.9, 10.5, 12.6, 15.2, 16.1, 17.7, 18.5, 19.8, 20.2, 21.7, 22 [4- (3-Fluoro-5-trifluoromethyl-pyridine, characterized by X-ray diffraction peaks obtained with CuKα irradiation, expressed in .9, 24.2 and 25.9 (± 0.2)] 2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone methylparaben co-crystal Form.   [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methane, characterized by the X-ray diffraction pattern substantially shown in FIG. Methylparaben co-crystal form of sulfonyl-2-((S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone. 3154, 3081, 1709, 1614, 1586, 1378, 1337, 1313, 1247, 1189, 1172, 1124, 1085, 1019, 959, 928, 916, 908, 894, 857, 783, 772, 729 and 702 cm ⁻¹ ( [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl, characterized by an infrared spectrum having a sharp band at ± 3 cm ⁻¹ ) 2-((S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone methylparaben co-crystal form.   [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl--characterized by the infrared spectrum substantially shown in FIG. Methyl paraben co-crystal form of 2-((S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone.   Compound: [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl], wherein at least 70% is in the form of any one of claims 1-22. -[5-Methanesulfonyl-2-((S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone. -After seeding, [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2 , 2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone,
-Or [4- (3-fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S)- Recrystallizing 2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone and spontaneously crystallizing below about 40 ° C .;
[4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2) , 2-Trifluoro-1-methyl-ethoxy) -phenyl] -methanone crystal form A. -[4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro Putting seed crystals into a solution of -1-methyl-ethoxy) -phenyl] -methanone;
-Or [4- (3-fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S)- Crystallizing a solution of 2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone,
-Or [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S)-) in one or more solvents Recrystallizing 2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone and adding seeds of form B;
[4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2) , 2-Trifluoro-1-methyl-ethoxy) -phenyl] -methanone crystal form B. -[4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro Crystallizing -1-methyl-ethoxy) -phenyl] -methanone;
-Or by adding a seed crystal of Form C, [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-(( S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone,
-Or [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2) at about 150 <0> C. , 2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone and chilled,
[4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2) , 2-Trifluoro-1-methyl-ethoxy) -phenyl] -methanone crystal form C. -[4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro Rapid evaporation from a solution of -1-methyl-ethoxy) -phenyl] -methanone under reduced pressure at about 40 ° C .;
-Or [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-tri Lyophilizing a solution of fluoro-1-methyl-ethoxy) -phenyl] -methanone;
[4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2) , 2-Trifluoro-1-methyl-ethoxy) -phenyl] -methanone in an amorphous form. -Digestion in a solvent;
Recrystallizing Form A, B, C or amorphous form and methylparaben with or without seed crystals in the solvent system,
[4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2) , 2-Trifluoro-1-methyl-ethoxy) -phenyl] -methanone in a methylparaben co-crystal form.   29. A compound prepared by any one of the methods of claims 24-28: [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5 -Methanesulfonyl-2-((S) -2,2,2-trifluoro-1-methyl-ethoxy) -phenyl] -methanone.   [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro- 1-Methyl-ethoxy) -phenyl] -methanone crystalline form A, B, C or an amorphous form or a methylparaben co-crystal form as an active ingredient.   24. A compound according to any one of claims 1 to 23 for use as a therapeutically active substance.   To produce a medicament useful for the treatment of psychosis, pain, neurodegenerative dysfunction in memory and learning, schizophrenia, dementia, and other diseases in which cognitive processes are impaired, such as attention deficit disorder or Alzheimer's disease [4- (3-Fluoro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]-[5-methanesulfonyl-2-((S) -2,2,2-trifluoro- Use of crystalline form A, B, C or amorphous form of 1-methyl-ethoxy) -phenyl] -methanone or methylparaben co-crystal form.   The invention described herein.